There is growing evidence that the host genetic make-up of an individual is a strong determinant of HIV/AIDS susceptibility during untreated HIV infection and immune recovery during highly active antiretroviral therapy (HAART). We will use state-of-the-art powerful genetic and statistical tools and targeted candidate gene approaches to identify genetic factors that influence HIV-AIDS susceptibility as well as immune recovery during highly active antiretroviral therapy (HAART) in a large cohort of adults from the VA, namely VA Aging Cohort Study (VACS). These studies will thus (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis and immune recovery during HAART in vivo; (b) determine the relative contribution to these determinants to the HIV-1 epidemic at the population level; (c) translate these findings to real life practical issues such as improved clinical care of patients via genetic-based prognostication of AIDS as well as immune recovery during HAART; and (d) the influence of alcohol and age in immune depletion/recovery. In the current application we will test the overall hypothesis that (I) expression of members of the CD4 - CD4 ligand - CCR5 - CCR5 ligand nexus, including relevant transducers of coreceptor signals, will alter HIV/AIDS susceptibility and immune recovery during HAART (aim #1); (II) expression of and interaction between selected candidate genes that influence innate and adaptive immune responses will alter HIV-AIDS susceptibility and immune recovery during HAART (aim #2). These include genes (i) at the MHC and KIR locus; (ii) encoding cellular intrinsic factors (TRIM5 and Apobec3 family); (iii) involved in the HIV life cycle such as PPIA and TSG101; (iv) identified as HIV dependency factors (HDF), and (iv) Copy Number Variation (CNV) at the chemokine gene-rich locus on chromosome 17q12, complement components (C4A and C4B), Fc receptors (FCGR3), and defensins. Thus, this proposal seeks approval for the use of specimens at VA Central biorepository to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility and immune recovery during HAART by amalgamating the unique skills and resources of the research teams at the VA Center for AIDS and HIV Infection at San Antonio, TX (PI: Dr Ahuja) and Yale University School of Medicine, New Haven, CT (PI: Dr Justice). PUBLIC HEALTH RELEVANCE: The studies proposed will provide new insights into the host factors that influence susceptibility to HIV and AIDS, and these findings could provide new ways to develop therapies and vaccines.